HexB genes

Sandhoff s disease is due to a deficiency of the HexB gene. Clinical features are similar to those of Tay-Sachs disease. Late infantile, juvenile and adults variants have also been described. 

Hexosaminidase A, the enzyme defective in Tay-Sachs disease, is actually composed of two subunits, an a and a 3 chain. The exact stoichiometry of the active enzyme is unknown, but it may be aiPi- The a subunit is coded for by the HexA gene, whereas the p subunit is coded for by the HexB gene. In Tay-Sachs disease, the a subunit is defective, and hexosaminidase A activity is lost. However, the p subunit can form active tetramers in the absence of the a subunit, and this activity, named hexosaminidase B, which cleaves the glycolipid globoside, retains activity in children with Tay-Sachs disease. Thus, children with Tay-Sachs disease accumulate the ganglioside GM2, but not globoside (Fig. 30.17). 

Mutation of the HexB gene, and production of a defective p subunit, leads to inactivation of both hexosaminidase A and B activity. Such a mutation leads to Sandhoff disease. Both activities are lost because both activities require a functional P subunit. The clinical course of this disease is similar to Tay-Sachs but with an accelerated timetable because of the initial accumulation of both GM2 and globoside in the lysosomes. 

Neote, K., Bapat, B., Dumbrille-Ross, A., Troxel, C., Schuster, S. M., Mahuran, D. J., and Gravel, R. A., 1988, Characterization of the human HEXB gene encoding lysosomal p-hexosaminidase, Genomics 3 279-286. 

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